This program-project grant seeks and enhanced understanding of the nature of the carcinogenic processes induced by chemicals. Three of the projects are directed primarily toward a better understanding of events related to the initiation of tumors by chemicals, two will provide a better understanding of the post- initiation stages of carcinogenesis, and the sixth has implications for both the initiation and post-initiation stages. The studies in the Millers' laboratory are directed particularly toward the identification of the electrophilic metabolites of chemical carcinogens that are of major importance to specific carcinogenic process and to the characterization of the reaction products of these metabolites with cellular macromolecules, especially DNA. Dr. Kasper's studies will provide a better biochemical understanding of the structures of the cytochromes P-450, NADPH-cytochrome P-450 oxidoreductase, and epoxide hydrolase and of the regulation of their activities in vivo at both the transcriptional and translational levels. These data are of great importance in view of the involvement of these enzymes in the activation and/or deactivation of a wide variety of chemical carcinogens. Dr. Fahl's research seeks a detailed understanding of the role of glutathione S-transferase-catalyzed reactions in reducing the effective levels of electrophiles formed from carcinogens in target cells and in thereby decreasing the susceptibility of the cells to mutagenesis or carcinogenesis. Dr Drinkwater is exploring genetic factors that predispose mice to the development of gross hepatomas through enhancing the rate of growth of microscopic foci of enzyme-altered cells and/or hepatomas. Dr. Pitot will analyze sequential changes in enzyme- altered hepatocytes during the progression stage of rat hepatocarcinogenesis. He will also study the regulation of transcription and the stability of specific mRNAs in hepatocytes. Dr. Poland will search for variants of the Ah receptor in human lymphoblastoid cell lines and examine the functional significance of these variants. This integrated research program will utilize chemical, biochemical, molecular biological, and biological approaches to develop a better understanding of chemical carcinogenesis.